Inhibition of the (H+/K+)ATPase proton pump, located in the gastric secretory membranes, has been a target for controlling gastric acid secretion in the treatment of ulcers.
Several families of compounds have been described as gastric acid secretion inhibitors, including heterocyclylalkylsulfinylbenzimidazoles (see U.S. Pat. Nos. 4,472,409, 4,394,509, 4,337,257, 4,327,102, 4,255,431, 4,045,564, 4,045,563 and 4,772,619; British Patent No. 2,134,523; and German Offenlegungsschrift No. 3,415,971) and heterocyclylalkylsulfinylnaphth[2,3-d]imidazoles (see U.S. Pat. Nos. 4,248,880 and 4,182,766). Similarly, other substituted benzimidazoles having a ring fused to the benzimidazole group have been described as gastric acid secretion inhibitors and cytoprotective agents. See EP Nos. 130,729 and 127,763.
Some heterocyclylalkylsulfinylbenzimidazoles have also been described as cytoprotective agents. See U.S. Pat. No. 4,359,465 and Great Britain Application 2,161,160, published Jan. 8, 1986. Omeprazole is an example of a class of benzimidazoles which inhibit the proton pump [Lindberg et al, Trends in Pharmaceutical Sciences, 399 (1987)].
It has been described that inhibitors of sodium transport reduce virus yields [A. A. Altamirano et al, Virology, 199, 151 (1994)]. There have been reports of isolated natural products which have been independently described as having (H+/K+) ATPase inhibitors and antiviral activity. T. Hayashi et al describe the isolation of scopadulcic acid B and its activity against (H+/K+)ATPase [Chem. Pharm. Bull., 38, 2740 (1990)] and HSV-1 [Chem. Pharm. Bull., 38, 239 (1990) and Antiviral Res., 9, 345 (1988)]. Pumilacidins are a class of heptapeptide antibiotics that have been isolated and described as being inhibitory to HSV-1 as well as (H+/K+)ATPase [N. Naruse et al, J. Antibiotics, 43, 267 (1990)].
There is a great need for new therapies active in the treatment of viral diseases. Whereas there has been great progress in developing a variety of therapies for the treatment of bacterial infections, there are few viable therapies for the treatment of viruses. Zidovudine is the primary approved treatment for human immunodeficiency virus. Ganciclovir, acyclovir and foscarnet are currently utilized for the treatment of herpesvirus infections. However, these therapies can have substantial side effects based on their deleterious effects on host cell DNA replication or effect of a limited number of viral infections. In addition, viruses are known to develop resistance to therapies which causes a progressive decline in efficacy [Ljungman et al., J. Infect. Dis., 162, 244 (1990) and Gately et al, J. Infect. Dis., 161, 711 (1990)].
Herpesviridae is a family of DNA viruses which include herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV6), human herpesvirus-7 (HHV7), pseudorabies and rhinotracheitis, among others.
It is known that herpesviruses express their genetic content by directing the synthesis of a number of proteins encoded by the herpesvirus DNA in the host cell. One of the important virus encoded proteins is made as a precursor consisting of an amino terminal-located protease and carboxyl terminal-located assembly protein. This precursor is proteolytically processed in an autocatalytic manner at a specific amino acid sequence known as the “release” site yielding separate protease and assembly protein. The assembly protein is cleaved further by the protease at another specific amino acid sequence known as the “maturation” cleavage site. Recently, EP No. 514,830, published Nov. 25, 1992, describes a virus-specific serine protease which has a role in herpesvirus replication. Additionally, Lui and Roizman (J. Virol, 65, 5149 (1991)) describe the sequence and activity of a protease and the associated assembly protein encoded by UL26 of HSV-1. A. R. Welch et al (Proc. Natl. Acad. Sci. USA, 88, 10792 (1991)) describe the related protease (also known as assemblin) and assembly protein encoded by UL80 of CMV. An approach currently being investigated for potential use in the treatment of herpesvirus infections is the development of inhibitors of herpesvirus proteases.
U.S. Pat. No. 4,371,537 describes sulfur substituted phenoxypyridines as having activity against RNA viruses, and specifically describes 2,5-bis(benzylthio)pyridine.
Benzimidazoles have been investigated for antiviral activity [R. W. Sidwell and J. T. Witkowski, Antiviral Agents, in BURGER'S MEDICINAL CHEMISTRY, PART II (M. Wolff, 4th ed. 1979)]. Specifically, 2-(α-hydroxybenzyl benzimidazole is described as a selective inhibitor of RNA enteroviruses.
EP No. 335,646, published Oct. 4, 1989, describes sulfur-containing compounds as having activity against rhinoviruses and coxsaki virus. Specifically, 5-[7-(benzimidazol-2-yl)sulfoxyheptyl]-3-methylisoxazole is described.
EP 407,217, published Jan., 9, 1991, describes compounds as having activity against RNA viruses. 2-[6-(2-chloro-4-methoxyphenoxy)-1-hexylthio]-benzimidazole is specifically described.
DE 3891468, published Feb. 24, 1994, describes prophylactic anti-herpesvirus activity of 6-bromo-5-hydroxy-4-dimethylaminomethyl-1-methyl-2-phenylthiomethylindol-3-carboxylic acid ethyl ester.
Polysubstituted benzimidazoles with activity against viruses of the herpes family are described in WO 92/07867. 2-Benzylthio-5,6-dichloro-1-(β-D-ribofuranosyl)benzimidazole is specifically described.